Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody

Abstract

Tick-borne encephalitis virus (TBEV) causes 13,000 cases of human meningitis and encephalitis annually. However, the structure of the TBEV virion and its interactions with antibodies are unknown. Here, we present cryo-EM structures of the native TBEV virion and its complex with Fab fragments of neutralizing antibody 19/1786. Flavivirus genome delivery depends on membrane fusion that is triggered at low pH. The virion structure indicates that the repulsive interactions of histidine side chains, which become protonated at low pH, may contribute to the disruption of heterotetramers of the TBEV envelope and membrane proteins and induce detachment of the envelope protein ectodomains from the virus membrane. The Fab fragments bind to 120 out of the 180 envelope glycoproteins of the TBEV virion. Unlike most of the previously studied flavivirus-neutralizing antibodies, the Fab fragments do not lock the E-proteins in the native-like arrangement, but interfere with the process of virusinduced membrane fusion.

Molecular Basis of a Protective/Neutralizing Monoclonal Antibody Targeting Envelope Proteins of both Tick-Borne Encephalitis Virus and Louping Ill Virus

“…Here, we present the crystal structures of LIV E as well as MAb 4.2 scFv in complex with the E protein of either LIV or TBEV. Structural analysis revealed that MAb 4.2 recognizes the lateral ridge of DIII on both E proteins, a hot spot for potent neutralizing antibodies against flaviviruses, as previously reported (6,21,(25)(26)(27)29). Further structural comparison and modeling imply that MAb 4.2 may function by preventing structural rearrangement during the virus-host membrane fusion process.…”

“…To date, the crystal structures of several lateral ridge-targeted neutralizing MAbs bound to MBFV E proteins have been reported, as exemplified by E16 for WNV, E106 for DENV1, and ZV67 for ZIKV (25-30, 48, 49). In addition, the cryo-EM structure of the TBEV virion in complex with a lateral ridge-targeting MAb, 19/1786, was recently reported (6). Further comparison reveals that the epitope of MAb 4.2 overlaps these MAbs (Fig.…”

“…In contrast, TBEV usually causes encephalitis only in humans, though it can also infect small rodents. TBEV is the most widespread TBFV, and TBEV is believed to annually cause 10,000 to 14,000 cases of infection across the Eurasia continent (6)(7)(8)(9). There are three main subtypes of TBEV (the central Europe subtype, the Siberia subtype, and the Far East subtype), from which the rate of mortality varies from 1 to 40% (1,3,5,(10)(11)(12)(13)(14).…”

“…Currently, no specific therapeutics are available (16). Monoclonal antibody (MAb)-based immunotherapy represents a promising antiviral approach against TBFVs (6), though the use of anti-TBEV immunoglobulins for tick-borne encephalitis (TBE) therapy was discontinued in Europe due to potential antibody-dependent enhancement (ADE) (17)(18)(19).…”

“…DIII is reported to contain epitopes for many potent MAbs, such as E16 for WNV (25), E106 for DENV serotype 1 (DENV1) (26), and ZV67 (27), Z23 (28), Z006 (29), and ZAV190 (30) for ZIKV. Recently, the cryo-electron microscopy (cryo-EM) structures of the TBEV virion and its complex with the neutralizing MAb 19/1786 were determined (6). Further, we previously reported a murine monoclonal antibody (MAb 4.2) that can prophylactically and therapeutically protect mice against LIV challenge (11).…”